Skin melanin is produced by melanocytes which locate in stratum of epidermis. Human skin usually have similar level of melanocytes, however, different population may have variation of melanin gene expression. Melanin is an insoluble high molecular weight polymer with compact molecular structure, which binds to protein very often. Based on its structure, melanin can be grouped into eumelanins, pheomelanins and allomelanins. Melanin in mammals is a mixed population of eumelanins and pheomelanins in various ratios. The quantities and types of these two kinds of melanin are controlled by 4 to 6 genes through incomplete dominant inheritance. Each gene copy is derived from both parents who express different skin colors after combination.
Melanin synthesis requires several enzymes and molecules for biochemical reactions, such as tyrosine, tyrosinase and oxygen. Tyrosinase oxidizes tyrosine into dihydroxyphenylalanine, transforms it to dopachrome, indoles, and finally melanin (Wulf, et al. Skin aging and natural photoprotection. 2004 Micron, 35, 185-191). Rate limiting step of that reaction is the step that the catalyzing by tyrosinase from dihydroxyphenylalanine into dopachrome. Auto-oxidation of dopachrome produces melanin. Tyrosinase is a copper containing metal enzyme, which is synthesized by melanocytes. Tyrosinase plays a very important role of melanin production. When tyrosinase activity increases, melanin production increases. On the contrary, when tyrosinase activity is inhibited, the ability of melanocyte producing melanin drops accordingly.
There are many reasons cause melanin precipitation. The elevation of tyrosinase activity leads to melanin synthesis when skin is exposed to UV radiation. Copper concentration elevation in blood also increases tyrosinase activity. Therefore, inhibition of tyrosinase activity is one way to reduce melanin synthesis.
The mechanism of melanin formation inhibition can be grouped into four categories: 1. reducing tyrosinase activity to inhibit melanin synthesis such as tyrosinase inhibitor; 2. minimizing melanocyte function with cytotoxic material to reduce melanocyte proliferation or make it unable to produce melanin; 3. reducing or preventing dihydroxyphenylalanine auto-oxidation such as anti-oxidant; and 4. inhibiting skin inflammation such as inflammatory swelling reaction after sun exposure. Therefore, for skin whitening cosmetology usage, one can block UV, remove free radicals, inhibit tyrosinase synthesis, inhibit tyrosinase activity and block melanin synthesis or fasten its metabolism and etc.
More patents have been found as tyrosinase inhibitors based on the first mechanism. Brief description is shown below. U.S. Pat. No. 5,723,109 used salicylic acid derivative as tyrosinase inhibitor, and U.S. Pat. No. 5,730,962 revealed a synthetic benzofuran and its derivatives for tyrosinase inhibition.
Several natural plant or food extracts also have tyrosinase inhibition effects. U.S. Pat. No. 5,824,320 reveals an extract and its derivatives from Aphloia and Mangifera leaf, which inhibits tyrosinase and collagenase activity. U.S. Pat. No. 5,968,487 provides a synthetic 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl 2-oxothiazolidine-4-carboxylate to inhibit human melanin synthesis as skin whitening agent. U.S. Pat. No. 6,750,229 provides a soybean extracted STI and Bowman-Birk protease inhibitor, which Bowman-Birk protease inhibitor functions on upper epidermis showing significant melanin inhibition along with increasing concentration. The melanin inhibition reaches more than 40% when combining these two extracts on pigs.
As described above, there are several pharmaceuticals can be used for whitening cosmetic agents. However, applying these whitening cosmetic ingredients alone shows weak effect. The product stability or safety issues such as skin irritation are not satisfactory for market demand. For example, it is known that ascorbic acid is not stable and easy to induce dermatitis. Kojic Acid and its derivatives have strong whitening effect but are easy to degrade under light or heat exposure. Hydroquinone has strong whitening effect but low stability. It also has discoloring issues during cosmetic production such as micelle and lotion as well as issues of inducing allergic contact dermatitis. Regarding biophamaceuticals such as GuangDong Ginseng, it is too pricey to generate low cost whitening agent for regular consumers.
In summary, there are still demands on compositions with excellent whitening effect at low dose or compositions with good safety and stability without skin irritation, and compositions easy to take or combine with food, cosmetics, and pharmaceuticals.